Microscopic colitis (MC) is a chronic condition that is a common cause of watery diarrhea, particularly in the elderly. The etiology is unknown but widely considered to be an abnormal immune reaction to luminal antigens in predisposed hosts. Drugs and autoimmunity have also been implicated. Although the incidence is comparable to ulcerative colitis and Crohn's disease, there are currently no funded NIH studies of microscopic colitis. In order to advance our understanding of MC, the proposed study will include rigorously and quantitatively defined cases, adequate controls, and extensive exposure information. The aims of the study are: 1) To quantitatively classify microscopic colitis using image analysis microscopy to determine whether the degree of lymphocytic infiltration correlates with etiology, symptoms and prognosis. 2) To investigate the etiology of microscopic colitis by examining medical and lifestyle risk factors including medications, autoimmunity, diet, and smoking 3) To evaluate the association between the adherent microbial flora and MC to assess whether bacterial dysbiosis is linked to presence of MC. As an exploratory aim we will evaluate whether CYP2C19 polymorphisms are more common in purportedly drug-induced disease since the diverse drugs that have been associated with MC are all substrates for this gene. To conduct the study we will obtain detailed dietary, medical and lifestyle information on study subjects who undergo complete colonoscopy for diarrhea. We will obtain colon biopsies from the right, transverse and left colon to evaluate adherent bacterial organisms. We will draw blood to evaluate CYP2C19 polymorphisms and for future genetic studies. The prospective design corrects important limitations of prior research on MC. The proposed study will use methods for colonoscopy-based studies that we have perfected over two decades. Successful completion of the study aims will improve our understanding of risk factors, set the stage for more scientificall grounded future research, and potentially suggest new interventions for a disease that is currently poorly understood.